The purpose of this project is to assess the effects of aging at a behavioral level of analysis, to identify neurobiological mechanisms associated with these effects, and to test interventions that might alter age-related performance decrements. Rodent models are tested in a battery of sensorimotor and learning/memory tasks. Neurochemical and neurohistological assays are conducted to determine neurobiological correlates of functional losses. Interventions include dietary restriction exercise, various pharmacologic treatments, neurotrophic factors and gene transfer via adenoviral vectors. Multiple genotypes are examined to determine possible genetic involvement in the pattern of age-related behavioral impairment. We have identified various effective pharmacologic strategies for improving learning performance of aged rats using manipulations of the cholinergic and glutamatergic neurotransmitter systems. We have also observed that circulatory problems possibly involving enlarged erythrocytes may be responsible for cognitive impairment in aged rats. Use of nitric oxide generating compounds to enhance vasodilation may be a useful strategy for alleviating this problem. We are also examining inflammatory responses in the aged brain and have noted enhanced cytokine responses in aged mice following endotoxin stress. Regarding impaired motor performance, we have continued development of an adenoviral vector for gene transfer of the dopamine D2 receptor.